The complement system which is composed of some 20 serum proteins plays an important role in the human immune system, both in the resistance to infections and in the pathogenesis of tissue injury. Conversely, inappropriate activation of complement can result in tissue injury and disease. For example, Type II membranoproliferative glomerulonephritis is associated with activation of the alternate complement pathway, possibly by a serum factor termed "C3 nephritic factor" or "C3NeF" which acts at the same step as properdin (Pathologic Basis of Disease, Second Ed., 1979, Robbins SL and Cotran RS, eds., W.B. Saunders Company, Philadelphia, pp. 1142-1143). Although many of the complement proteins have been cloned and their roles in the complement system determined, no satisfactory method of controlling complement-associated disorders currently exists.
The complement system is largely regulated by the inactivation of its activated components. Activated complement components are inactivated through spontaneous decay and through their association(s) with specific binding proteins and/or proteases. For example, C4b-binding protein forms a complex with Factor I that proteolytically inactivates C4b, which thereby reduces C3 convertase activity and C5 convertase activity, both of which comprise C4b. Also for example, antagonist proteins may bind to complement components, such as C3b or C4b, thereby inhibiting their intermolecular association(s) with other complement components necessary to form activated complement convertase complexes.
Complement activation can account for substantial tissue damage in a wide variety of autoimmune/immune complex mediated syndromes such as systemic lupus erythematosus, rheumatoid arthritis, hemolytic anemias, myasthenia gravis and others. Inhibition of the complement system is likely to be desirable therapeutic intervention in these cases. In some instances, specific inhibition of the classical pathway alone could be preferred since long-term inhibition of the alternative pathway could lead to grave side effects.
Inhibition of complement activation could also be desirable in cases that involve tissue damage brought about by vascular injury such as myocardial infarction, cerebral vascular accidents or acute shock lung syndrome. In these cases, the complement system may contribute to the destruction of partially damaged tissue as in reperfusion injury. Highly stringent inhibition of complement for relatively brief periods might be preferred in these instances. In addition, the use of complement protease analogs with novel target specificities could reduce the activity of tissue-damaging proteins at sites of inflammation. Complement inhibition is important in the prevention of xenograft rejection. The inhibition of complement by cell-associated and soluble inhibitors is useful in protecting the transplant from damage caused by activation of endogenous complement.
Recently, a soluble form of the complement receptor CR1, a member of the regulators of complement activation protein family, has been used to inhibit various complement-mediated injuries (Weisman et al. (1990) Science 249: 146; Yeh et al. (1991) J. Immunology 146: 250; Pruitt et al. (1991) Transplantation 52: 868; Mulligan et al. (1992) J. Immunology 148: 1479). However, other regulators of complement activation already exist in soluble form and many of the complement proteins other than CR1 can be targeted to affect the regulation of the system and in different ways than producing soluble receptors.
Based on the foregoing, it is clear that a need exists for a method of preventing or controlling inappropriate complement activation that results in tissue injury and disease. This application provides the design and construction of new modified forms of complement proteases, whose administration could alter complement activation and thus have therapeutic use in humans.